Biochemical Evaluation of a 108-Member Deglycobleomycin Library: Viability of a Selection Strategy for Identifying Bleomycin Analogues with Altered Properties

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• 作者：Qian Ma ; Zhidong Xu ; Benjamin R. Schroeder ; Wenyue Sun ; Fang Wei ; Shigeki Hashimoto ; Kazuhide Konishi ; Christopher J. Leitheiser ; Sidney M. Hecht
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：October 17, 2007
• 年：2007
• 卷：129
• 期：41
• 页码：12439 - 12452
• 全文大小：888K
• 年卷期：v.129,no.41(October 17, 2007)
• ISSN：1520-5126

文摘

The bleomycins (BLMs) are clinically used glycopeptide antitumor antibiotics that have beenshown to mediate the sequence-selective oxidative damage of both DNA and RNA. Previously, we describedthe solid-phase synthesis of a library of 108 unique analogues of deglycoBLM A₆, a congener that cleavesDNA analogously to BLM itself. Each member of the library was assayed for its ability to effect single- anddouble-strand nicking of duplex DNA, sequence-selective DNA cleavage, and RNA cleavage in the presenceand absence of a metal ion cofactor. All of the analogues tested were found to mediate concentration-dependent plasmid DNA relaxation to some extent, and a number exhibited double-strand cleavage withan efficiency comparable to or greater than deglycoBLM A₆. Further, some analogues having altered linkerand metal-binding domains mediated altered sequence-selective cleavage, and a few were found to cleavea tRNA₃^Lys transcript both in the presence and in the absence of a metal cofactor. The results provideinsights into structural elements within BLM that control DNA and RNA cleavage. The present study alsopermits inferences to be drawn regarding the practicality of a selection strategy for the solid-phaseconstruction and evaluation of large libraries of BLM analogues having altered properties.